The long-range research goal is to develop a new drug to treat secondary (central nervous system) stage human African trypanosomiasis. Previous SBIR supported research identified DB289, a methoxime prodrug of the aromatic dication furamidine, that is currently progressing in Phase lib clinical trials for treatment of early stage African sleeping sickness. DB289, however, is not curative in animal models of CNS stage trypanosomiasis. We have recently identified alkylamidoxime prodrugs of novel aza analogs of furamidine that are curative in a chronic mouse model of infection. The objective of this Phase I SBIR application is to synthesize sufficient quantities of six prodrugs to perform further efficacy, toxicity and metabolism studies. The specific aims are designed to permit selection of a lead candidate compound to enroll during Phase II research into advanced efficacy testing in a primate model of CNS infection and into formal preclinical toxicity testing. The research may lead to development of a potent, safe and economical new drug to treat this devastating protozoan parasitic infection currently estimated to be killing over 300,000 people in recent outbreaks in Africa.